Magnetized Aerosols Comprising Superparamagnetic Iron Oxide Nanoparticles Improve Targeted Drug and Gene Delivery to the Lung

ABSTRACTPurposeTargeted delivery of aerosols could not only improve efficacy of inhaled drugs but also reduce side effects resulting from their accumulation in healthy tissue. Here we investigated the impact of magnetized aerosols on model drug accumulation and transgene expression in magnetically targeted lung regions of unanesthetized mice.MethodsSolutions containing superparamagnetic iron oxide nanoparticles (SPIONs) and model drugs (fluorescein or complexed plasmid DNA) were nebulized to unanesthetized mice under the influence of an external magnetic gradient directed to the lungs. Drug accumulation and transgene expression was subsequently measured at different time points.ResultsWe could demonstrate 2–3 fold higher accumulation of the model drug fluorescein and specific transgene expression in lung regions of mice which had been exposed to an external magnetic gradient during nebulization compared to the control mice without any exposure to magnetic gradient.ConclusionsMagnetized aerosols present themselves as an efficient approach for targeted pulmonary delivery of drugs and gene therapeutic agents in order to treat localized diseases of the deeper airways.

[1]  S. Wong,et al.  Luciferin detection after intranasal vector delivery is improved by intranasal rather than intraperitoneal luciferin administration. , 2008, Human gene therapy.

[2]  R. Coleman,et al.  Aerosol delivery in intubated, mechanically ventilated patients , 1985, Critical care medicine.

[3]  J. Heyder,et al.  Mucociliary and long-term particle clearance in airways of patients with immotile cilia , 2006, Respiratory research.

[4]  C. Rudolph,et al.  Magnetic aerosol targeting of nanoparticles to cancer: nanomagnetosols. , 2010, Methods in molecular biology.

[5]  A. Hershey,et al.  Inhalation chemotherapy for macroscopic primary or metastatic lung tumors: proof of principle using dogs with spontaneously occurring tumors as a model. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  E. Golunski,et al.  Improved respiratory delivery of the anticancer drugs, camptothecin and paclitaxel, with 5% CO2-enriched air: pharmacokinetic studies , 2001, Cancer Chemotherapy and Pharmacology.

[7]  E. Golunski,et al.  Paclitaxel liposome aerosol treatment induces inhibition of pulmonary metastases in murine renal carcinoma model. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  Christian Plank,et al.  Generation of magnetic nonviral gene transfer agents and magnetofection in vitro , 2007, Nature Protocols.

[9]  H. Stark,et al.  Aerosolized nanogram quantities of plasmid DNA mediate highly efficient gene delivery to mouse airway epithelium. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  G. Peters,et al.  Phase I Study of Aerosolized SLIT Cisplatin in the Treatment of Patients with Carcinoma of the Lung , 2007, Clinical Cancer Research.

[11]  J. Rosenecker,et al.  Methodological optimization of polyethylenimine (PEI)‐based gene delivery to the lungs of mice via aerosol application , 2005, The journal of gene medicine.

[12]  Bernhard Gleich,et al.  Targeted delivery of magnetic aerosol droplets to the lung , 2007, Nature Nanotechnology.

[13]  W. Erhardt,et al.  Magnetisches Drug Targeting—ein neuer Ansatz in der lokoregionären Tumortherapie mit Chemotherapeutika , 2005, HNO.

[14]  H. Shindo,et al.  Perfusion study of hypervascular hepatocellular carcinoma with SPIO. , 2005, Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine.

[15]  Wolfgang J Parak,et al.  Fluorescent-magnetic hybrid nanoparticles induce a dose-dependent increase in proinflammatory response in lung cells in vitro correlated with intracellular localization. , 2010, Small.

[16]  J. Heyder,et al.  Mucociliary and long-term particle clearance in the airways of healthy nonsmoker subjects. , 2004, Journal of applied physiology.

[17]  C. Rudolph,et al.  Targeting of the prostacyclin specific IP1 receptor in lungs with molecular conjugates comprising prostaglandin I2 analogues. , 2010, Biomaterials.

[18]  C. Rudolph,et al.  Targeting of the beta(2)-adrenoceptor increases nonviral gene delivery to pulmonary epithelial cells in vitro and lungs in vivo. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[19]  C Alexiou,et al.  [Magnetic Drug Targeting--a new approach in locoregional tumor therapy with chemotherapeutic agents. Experimental animal studies]. , 2005, HNO.

[20]  C. Rudolph,et al.  Targeted gene delivery to the lung , 2009, Expert opinion on drug delivery.

[21]  J. Heyder,et al.  Human alveolar long-term clearance of ferromagnetic iron oxide microparticles in healthy and diseased subjects. , 2001, Experimental lung research.

[22]  Ching-Li Tseng,et al.  The use of biotinylated-EGF-modified gelatin nanoparticle carrier to enhance cisplatin accumulation in cancerous lungs via inhalation. , 2009, Biomaterials.

[23]  A. Hochberg,et al.  Aerosolized BC-819 Inhibits Primary but Not Secondary Lung Cancer Growth , 2011, PloS one.

[24]  J. Heyder,et al.  Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. , 2004, Proceedings of the American Thoracic Society.